Alzheimer's Disease (AD) is the leading cause of late-onset dementia and is characterized by progressive cognitive decline and memory loss, ultimately leading to death. Over 5 million Americans are currently suffering from AD, and the total costs of AD and other dementias exceed $145 billion annually. Understanding the pathogenesis of AD in order to ultimately develop effective treatments is therefore paramount and is the motivation for this research proposal. Accumulation of the amyloid beta (AP) peptide into oligomeric forms and insoluble amyloid plaques appears to play a critical role in AD pathogenesis. Conversion of soluble Ab into these toxic species is concentration-dependent. Thus, mechanisms that regulate the amount of Ab in the brain may act as key determinants of whether A (3will aggregate into toxic forms. Data from our laboratory and others have demonstrated that synaptic activity regulates Ab levels within the extracellular space of the brain (interstitial fluid - ISF). However, how ISF Ab levels change as a result of physiological alterations in synaptic activity is not known. Therefore, the objective of this proposal is to determine the effect of physiological manipulations that alter synaptic activity on ISF Ab levels in vivo. I hypothesize that physiological changes in neuronal activity dynamically regulate the release of Ab into the extracellular space of the brain. In Specific Aim 1,1 will stimulate the whiskers of a live mouse in order to elicit an acute increase in neuronal activity within the barrel cortex. During the stimulation period, I will use electrophysiological recording simultaneously with in vivo microdialysis in barrel cortex to measure neuronal activity and ISF Ab levels and observe how levels change during whisker stimulation. In Specific Aim 2, I will determine the effect of voluntary exercise on ISF Ab levels and neuronal activity in hippocampus and primary motor cortex by performing in vivo microdialysis with concurrent electrophysiological recording in these brain regions during exercise. I will also examine the effect of exercise on APP processing by extracting brains after exercise and measuring protein levels of APP derivatives by Western blot. In Specific Aim 3,1 will determine the effects of environmental enrichment on ISF Ab levels and neuronal activity using in vivo microdialysis and electrophysiological recording in the hippocampus following enrichment. Finally, I will use microdialysis to determine if enrichment alters Ab clearance from the extracellular space of the brain. Public Health Relevance: The relevance of this proposal to public health is that elucidating the mechanisms that regulate Ab levels in the brain under normal physiological conditions may provide novel insights into AD pathogenesis and may ultimately provide new opportunities for therapeutic intervention.